Abstract:Background: Medulloblastoma in adult patients is rare, with 0.6 cases per million. Prognosis depends on clinical factors and medulloblastoma entity. No prospective data on the feasibility of radio-chemotherapy exist. The German Neuro-Oncology Working Group (NOA) performed a prospective descriptive multicenter single-arm Phase II trial to evaluate feasibility and toxicity of radio-polychemotherapy. Methods: The NOA-07 trial combined cranio-spinal irradiation with vincristine, followed by eight cycles of cisplatin, lomustine and vincristine. Adverse events, imaging and progression patterns, histological and genetic markers, health-related quality of life (HRQoL) and cognition were evaluated. Primary endpoint was the rate of toxicityrelated treatment terminations after four chemotherapy cycles, and the toxicity profile. The feasibility goal was reached if at least 45% of patients received at least 4 cycles of maintenance chemotherapy. Results: Thirty patients were evaluable. Each 50% percent showed classic and desmoplastic-nodular histology. Sixty-seven percent were classified into the sonic hedgehog (SHH) subgroup without TP53 alterations, 13% in wingless (WNT), and 17% in Non-WNT/Non-SHH. Four cycles of chemotherapy were feasible in the majority (n=21; 70.0%). Hematological side effects and polyneuropathy were prevalent toxicities. During the active treatment period, HRQoL and verbal fluency improved significantly. The 3-year event-free survival rate (EFS) was 66.6% at the time of databank lock. Conclusions: Radio-polychemotherapy did lead to considerable toxicity and a high amount of dose reductions throughout the first four chemotherapy cycles that may affect efficacy. Thus, we propose frequent patient surveillance using this regimen.Modifications of the regimen may increase feasibility of radio-polychemotherapy of adult patients with medulloblastoma. Powered by Editorial Manager® and ProduXion Manager® from Aries Systems Corporation N-O-D-17-00180R1Dear Prof. Wen, many thanks for the opportunity to, for the second time, re-submit our above mentioned manuscript to NeuroOncology with major revisions.Below, you will find our point-to-point answer to all reviewer comments. Please be aware that there are two open questions where we will need the feedback of the acting editor and the reviewer, respectively.We declare that our manuscript, or any part of it, has not been previously published or submitted concurrently to any other journal, and that all co-authors have read and approved the revised version of the manuscript. We further declare that we agree to pay for full color reproduction.We hope that the revisions will now qualify the manuscript for publication in Neuro-Oncology. We will however be happy to address further questions, if indicated. . This hypothesis results in an exploratory and descriptive feasibility design, focusing on the rate of toxicity-related treatment terminations after 4 cycles of adjuvant chemotherapy. The statistical approach of this study therefore did not contain a formal H0/...

The in vivo activity and source of I-lactamase in sputum samples from 43 patients with cystic fibrosis (CF) during a 2-week antipseudomonal treatment were studied. A colorimetric method, based on the conversion of nitrocefin, was used for quantitation of the sputum ,B-lactamase activity. P-Lactamases in sputum were characterized by isoelectric focusing and inhibition profile and were compared with the ,-lactamases extracted from Pseudomonas aeruginosa isolated from the paired sputum samples. We found that the ,B-lactamase activity increased to high levels in sputum from patients with CF during the course of piperacillin, ceftazidime, cefsulodin, or imipenem therapy. Aztreonam therapy lead to opposite results because the j-lactamase activity decreased and aztreonam was able to mask j-lactamase activity by acting as an inhibitor. All sputum j-lactamases displayed characteristics indicative of a class I enzyme, identical to the (-lactamases extracted from P. aeruginosa. The presence of P-lactamase at such levels could lead to in vivo inactivation of j-lactam antibiotics. This study supports the hypothesis that P-lactamase production is an important in vivo resistance mechanism in P. aeruginosa-infected patients with CF.

Background Combined radiochemotherapy followed by maintenance chemotherapy with cisplatin, lomustine and vincristine within the NOA-07 study resulted in considerable short-term toxicity in adult medulloblastoma patients. Here we investigated the long-term impact of this treatment, focusing on neurocognitive functioning and health-related quality of life (HRQoL). Methods Neurocognitive functioning and HRQoL scores over time were determined, and differences between the posttreatment and follow-up assessments were calculated up to 18 months for neurocognition and 60 months for HRQoL. Results 28/30 patients were analyzed. The three preselected HRQoL scales (role, social and cognitive functioning) showed improved scores, to a clinically relevant extent (≥ 10 points), compared to post-treatment levels up to 30 months, but decreased afterwards. Z-scores for verbal working memory were worse during follow-up compared to post-treatment scores and remained impaired during 18 months follow-up (i.e. z-score below − 1 standard deviation). Attention was impaired post-treatment, and remained impaired to a clinically relevant extent during follow-up. Coordination/processing speed and lexical verbal fluency improved compared to post-treatment scores, and remained within the normal range thereafter. Other tests of verbal fluency were stable over time, with z-scores within the normal range. Conclusions This long-term follow-up study showed that the NOA-07 treatment regimen was not associated with a deterioration in HRQoL in the post-treatment period. Verbal working memory deteriorated, while other neurocognitive domains did not seem to be impacted negatively by the treatment.

Background The prognosis of patients with brain tumors is widely varying. Psychooncologic need and depression are high among these patients and their family caregivers. However, the need for counselling and need for referral to psychooncology care is often underestimated. Methods We performed a single-institution cross-sectional study to evaluate psychooncologic need, depression and information need in both patients and their family caregivers. The Hornheider Screening Instrument (HSI) and the Patient Health Questionnaire (PHQ-9) were used to evaluate psychooncologic need and depression, and a study-specific questionnaire was developed to evaluate information need. Multivariable analyses were performed to detect correlations. Results A total of 444 patients and their family caregivers were approached to participate, with a survey completion rate of 35.4%. More than half of the patients and family caregivers were in need for referral to psychooncology care and 31.9% of patients suffered from clinically relevant depression. In multivariable analysis, psychooncologic need were positively associated with mild (odds ratio, OR, 7.077; 95% confidence interval, CI, 2.263–22.137; p = 0.001) or moderate to severe (OR 149.27, 95% CI 26.690–737.20; p <  0.001) depression. Patient information need was associated with depression (OR 3.007, 95% CI 1.175–7.695; p = 0.022). Conclusions Unmet counselling need in brain tumor patients and their family caregivers associate to high psychooncologic need and depression. Adequate information may decrease the need for referral to psychooncology care and treatment of depression in these patients. Future studies should further explore these relations to promote development of supportive structures.

Abstracts iii3NEURO-ONCOLOGY • MAY 2017 of the prognostic significance of MGMT promoter methylation relative to IDH and 1p/19q status is ongoing as well as efforts to increase sample size. FUNDING: U10CA180868, U10CA180822, and U24CA196067 (NCI). Also, R01CA108633, R01CA169368, RC2CA148190, U10CA180850-01 (NCI), Brain Tumor Funders Collaborative Grant, and the Ohio State University CCC (all to AC). BACKGROUND: Medulloblastoma in adult patients has a low incidence, with 0.6 cases per million. Prognosis depends on clinical factors and medulloblastoma entity. In contrast to children, no prospective data on the feasibility of radio-chemotherapy in adults exists. The German Neuro-Oncology Working Group (NOA) performed a prospective multicenter single-arm Phase II trial to evaluate the feasibility and toxicity of radio-chemotherapy in this population. METHODS: The NOA-07 trial combined cranio-spinal irradiation with vincristine, followed by a maximum of eight cycles of cisplatin, lomustine and vincristine. Adverse events, imaging and progression patterns, combined histological and genetic markers, health-related quality of life (HRQoL) and cognition were evaluated prospectively. The primary endpoints were the rate of toxicity-related treatment terminations after four cycles of chemotherapy, and the toxicity profile. FINDINGS: Thirty patients were evaluable. Fifty percent of patients showed classic, and 50% desmoplastic-nodular histology. Sixty-eight percent of patients were genetically classified into the sonic hedgehog (SHH) subgroup without TP53 alterations, 13.6% in wingless (WNT), and 17.7% in Non-WNT/Non-SHH (Group 4). Four cycles of chemotherapy were feasible in the majority of patients (n=21; 70.0%). Leukopenia was the major toxicity, with 79 events of CTC grade 3 and 4 in 17 patients. Polyneuropathy and ototoxicity were the only grade 3 or 4 non-haematological toxicities during the active treatment phase and occurred 12 times in eight patients and one time in one patient, respectively. Events were also calculated per cycle and showed an increase of toxicity over treatment time. Feasibility appeared to be age-dependent, leading to application of four cycles of chemotherapy in 72.7% of patients below age 45 and 62.5% of patients 45 or above. Testing for all eight adjuvant cycles revealed that 45.5% of all patients younger than 45 years completed eight cycles, whereas only 12.5% of patients over 45 years received all cycles. Severe adverse events were significantly more frequent in patients older than 45 years of age (p = 0.040). We observed no treatment-related deaths. During the active treatment period, HRQoL showed clinically relevant improvements in several domains. Verbal fluency also improved. The 3-year EFS rate was 66.6% at the time of databank lock. INTERPRETATION: This is a prospective trial in a homogenous population of adults with medulloblastoma. Radio-chemotherapy was safe and tolerable throughout the active treatment phase and generated improvements of HRQoL and cognition. However, toxicity was ...